Cannabis use is prevalent in the US population, and its prevalence is likely to increase due to ongoing legalization efforts. Thus, understanding the implications (both beneficial and harmful) of long-term cannabis use is imperative. While the long-term cognitive and psychiatric sequelae of cannabis use have been intensely investigated, few studies have investigated the metabolic effects of long-term cannabis use. Metabolism is a likely target for cannabis as several of the compounds abundant in cannabis (e.g., delta-9- tetrahydrocannabinol, THC) directly affect feeding behaviors and/or metabolism. Interestingly, despite the popular view that cannabis ingestion enhances consumption of calorically dense food, which might lead to increased obesity, the metabolic syndrome, and type II diabetes among chronic cannabis users, most epidemiological studies have found the opposite. Thus, chronic cannabis use is associated with decreased body mass index, decreased incidence of metabolic syndrome, and a decreased risk for developing type II diabetes. The mechanism for this is unclear?stimulation of CB1 cannabinoid receptors by THC would be expected to increase consumption of calorically rich foods and increase fat deposition, thus it is likely that THC may target other receptor(s) involved in metabolism and whose engagement by THC leads to more beneficial metabolic effects. The proposed work will address the hypothesis that activation of GPR119 beneficial metabolic consequences. GPR119 is a G protein-coupled receptor expressed in pancreatic beta cells as well as K and L enteroendocrine cells in the gastrointestinal tract. Its activation increases insulin secretion from the pancreas, secretion of the incretins GIP and GLP-1, as well as PYY, from the gut, and may protect beta cells from apoptosis. Cumulatively, GPR119 activation is expected to lead to a favorable metabolic profile, which has made GPR119 activation a target for drug development. In preliminary studies investigating GPR119 signaling, we made the surprising observation that THC is a GPR119 agonist. Further studies found that chronic administration of THC or a GPR119 agonist decreased weight in obese mice to the same extent. In the proposed R21 CEBRA we will complete two specific aims to better understand the consequences of THC signaling through GPR119. Aim 1. Fully characterize the signaling of THC and other cannabinoids at GPR119 using cell lines natively expressing GPR119. Aim 2. Determine if THC-induced weight loss in obese mice requires GPR119. Completion of these two specific aims will greatly advance our understanding of the potential role of GPR119 in mediating the apparent metabolic benefits of THC.